Licence to kill senescent cells in idiopathic pulmonary fibrosis?

Mailleux, Arnaud; Crestani, Bruno

doi:10.1183/13993003.01360-2017

Cited by 15 publications

(14 citation statements)

References 38 publications

(64 reference statements)

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“…In line with this concept, the clearance of senescent cells favors the resolution of fibrosis and improves pulmonary function in mice (6,11,13,34). Therefore, targeting of these cells is recognized as a promising therapeutic approach for IPF (16,35,36).…”

Section: Discussionmentioning

confidence: 94%

Quercetin Enhances Ligand-induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung Fibrosis In Vivo

Hohmann

Habiel

Coelho

et al. 2019

Am J Respir Cell Mol Biol

156

121

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While cellular senescence may be a protective mechanism in modulating proliferative capacity, fibroblast senescence is now recognized as a key pathogenic mechanism in Idiopathic Pulmonary Fibrosis (IPF). In aged mice, abundance and persistence of apoptosis-resistant senescent fibroblasts play a central role in non-resolving lung fibrosis after bleomycin challenge. Therefore, we investigated whether quercetin can restore the susceptibility of senescent IPF fibroblasts to pro-apoptotic stimuli and mitigate bleomycin-induced pulmonary fibrosis in aged mice. Unlike senescent normal lung (NL) fibroblasts, IPF lung fibroblasts from patients with stable and rapidly progressing disease were highly resistant to Fas ligand (FasL) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Senescent IPF fibroblasts exhibited decreased expression of FasL and TRAIL receptors and caveolin-1, as well as increased AKT activation compared with senescent NL fibroblasts. Although, quercetin alone was not pro-apoptotic, it abolished the resistance to FasL- or TRAIL-induced apoptosis in IPF fibroblasts. Mechanistically, quercetin up regulated Fas and caveolin-1 expression, and modulated AKT activation. In vivo, quercetin reversed bleomycin-induced pulmonary fibrosis and attenuated lethality, weight loss, and the expression of pulmonary senescence markers p21 and p19-ARF and senescence-associated secretory phenotype (SASP) in aged mice. Collectively these data indicate that quercetin reverses the resistance to death ligand-induced apoptosis, by promoting FasL receptor and caveolin-1 expression, and inhibiting AKT activation, thus mitigating the progression of established pulmonary fibrosis in aged mice. Therefore, quercetin may be a viable therapeutic option for IPF and other age-related diseases that progress with the accumulation of senescent fibroblasts.

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Section: Discussionmentioning

confidence: 94%

Quercetin Enhances Ligand-induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung Fibrosis In Vivo

Hohmann

Habiel

Coelho

et al. 2019

Am J Respir Cell Mol Biol

156

121

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show abstract

“…Preliminary experiments in animal models suggest that clearing senescent cells should have a positive effect on healthspan and lifespan 19 , 20 , 37 , fibrosis 70 , hepatic steatosis 23 , vasomotor dysfunction 71 , pulmonary fibrosis 72 , osteoarthritis 72 and could improve the response to cancer therapies 73 . Our results indicate that antibodies could be an efficient system to bring toxic drugs into specific types of senescent cells in humans with minimal side effects, following up on the success of similar approaches in cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker

Poblocka

Bassey

Smith

et al. 2021

Sci Rep

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A wide range of diseases have been shown to be influenced by the accumulation of senescent cells, from fibrosis to diabetes, cancer, Alzheimer’s and other age-related pathologies. Consistent with this, clearance of senescent cells can prolong healthspan and lifespan in in vivo models. This provided a rationale for developing a new class of drugs, called senolytics, designed to selectively eliminate senescent cells in human tissues. The senolytics tested so far lack specificity and have significant off-target effects, suggesting that a targeted approach could be more clinically relevant. Here, we propose to use an extracellular epitope of B2M, a recently identified membrane marker of senescence, as a target for the specific delivery of toxic drugs into senescent cells. We show that an antibody–drug conjugate (ADC) against B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expression and therefore more evident in stress-induced senescence. Non-senescent cells were not affected by either antibody, confirming the specificity of the treatment. Our results provide a proof-of-principle assessment of a novel approach for the specific elimination of senescent cells using a second generation targeted senolytic against proteins of their surfaceome, which could have clinical applications in pathological ageing and associated diseases.

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“…Senescent cells have been proposed to drive several diseases [28]. This includes IPF, where senescent cells showed a pro-inflammatory and pro-fibrotic phenotype [27,29,30].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Bioinformatics Identifies Key microRNA Players in ATG7-Deficient Lung Fibroblasts

Stojanović

Fuchs

Fiedler

et al. 2020

IJMS

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Background: Deficient autophagy has been recently implicated as a driver of pulmonary fibrosis, yet bioinformatics approaches to study this cellular process are lacking. Autophagy-related 5 and 7 (ATG5/ATG7) are critical elements of macro-autophagy. However, an alternative ATG5/ATG7-independent macro-autophagy pathway was recently discovered, its regulation being unknown. Using a bioinformatics proteome profiling analysis of ATG7-deficient human fibroblasts, we aimed to identify key microRNA (miR) regulators in autophagy. Method: We have generated ATG7-knockout MRC-5 fibroblasts and performed mass spectrometry to generate a large-scale proteomics dataset. We further quantified the interactions between various proteins combining bioinformatics molecular network reconstruction and functional enrichment analysis. The predicted key regulatory miRs were validated via quantitative polymerase chain reaction. Results: The functional enrichment analysis of the 26 deregulated proteins showed decreased cellular trafficking, increased mitophagy and senescence as the major overarching processes in ATG7-deficient lung fibroblasts. The 26 proteins reconstitute a protein interactome of 46 nodes and miR-regulated interactome of 834 nodes. The miR network shows three functional cluster modules around miR-16-5p, miR-17-5p and let-7a-5p related to multiple deregulated proteins. Confirming these results in a biological setting, serially passaged wild-type and autophagy-deficient fibroblasts displayed senescence-dependent expression profiles of miR-16-5p and miR-17-5p. Conclusions: We have developed a bioinformatics proteome profiling approach that successfully identifies biologically relevant miR regulators from a proteomics dataset of the ATG-7-deficient milieu in lung fibroblasts, and thus may be used to elucidate key molecular players in complex fibrotic pathological processes. The approach is not limited to a specific cell-type and disease, thus highlighting its high relevance in proteome and non-coding RNA research.

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Licence to kill senescent cells in idiopathic pulmonary fibrosis?

Cited by 15 publications

References 38 publications

Quercetin Enhances Ligand-induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung Fibrosis In Vivo

Quercetin Enhances Ligand-induced Apoptosis in Senescent Idiopathic Pulmonary Fibrosis Fibroblasts and Reduces Lung Fibrosis In Vivo

Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker

Comprehensive Bioinformatics Identifies Key microRNA Players in ATG7-Deficient Lung Fibroblasts

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